Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, UK.
Biomaterials. 2011 Feb;32(5):1370-6. doi: 10.1016/j.biomaterials.2010.10.037. Epub 2010 Nov 12.
Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.
纳米颗粒制剂为治疗试剂向肿瘤的输送提供了机会。受体靶向纳米复合物（RTN）制剂由聚乙二醇化的、内体可裂解的脂质和 RGD 整联蛋白靶向的、内体可裂解的肽组成。纳米复合物在与质粒 DNA 混合时自组装，产生约 100nm 的纳米颗粒。环境敏感的连接物促进 DNA 的细胞内解组装和释放。携带荧光素酶基因的 RTN 被静脉内给药给携带皮下神经母细胞瘤肿瘤的小鼠。与肝、脾和肺相比，肿瘤中的荧光素酶表达要高得多，而质粒分布研究支持表达数据。与非靶向纳米复合物相比，整合素靶向肽使肿瘤中的转染增强了两倍。含有白细胞介素-2 (IL-2) 和 IL-12 基因的 RTN 以 48 小时的间隔静脉内给予七剂，并监测肿瘤生长。与含有对照质粒的 RTN 相比，治疗动物的肿瘤在第 11 天缩小了约 75%，三分之一的治疗小鼠长期存活。在接受 IL2/IL12 治疗的动物的肿瘤中观察到大量白细胞浸润、血管生成减少和坏死区域增加。从重新挑战的小鼠中分离的脾细胞在与 Neuro-2A 共培养后显示出增强的 IL-2 产生，这与浸润研究一起表明存在细胞毒性 T 细胞介导的肿瘤排斥过程。整合素靶向 RTN 制剂可能在癌症治疗的进一步发展中有更广泛的应用。
